Pemetrexed formulations

Abstract

The present invention is directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable after dilution for at least about 48 hours when stored at 2° C. to 8° C. The present invention is also directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable for at least about 24 months when stored at 2° C. to 8° C.

What is claimed is: 
     
       1. A method of treating pleural mesothelioma or non-squamous, non-small cell lung cancer in a patient in need thereof comprising
 providing a liquid pharmaceutical composition consisting of: 
 20 mg/mL to 30 mg/mL of pemetrexed diacid; 
 200 mg/mL to 300 mg/mL of propylene glycol; 
 12 mg/mL to 24 mg/mL of tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6, wherein the composition is suitable for multi-dose administration, and wherein the composition remains stable when stored for about 14 months at a temperature of 2° ° C. to 8° C. in a container having a head-space oxygen content of about 20% v/v, such that the composition comprises no more than 3% w/w of total impurities after said storage;
 diluting the liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's Injection, or Lactated Ringer's Injection to form a diluted liquid composition; and 
 intravenously administering the diluted liquid composition to the patient. 
 
     
     
       2. The method of  claim 1 , wherein the liquid pharmaceutical composition consists of:
 25 mg/mL of the pemetrexed diacid; 
 250 mg/mL to 300 mg/mL of the propylene glycol; 
 17 mg/mL to 21 mg/mL of the tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6. 
     
     
       3. The method of  claim 1 , wherein the liquid pharmaceutical composition consists of:
 25 mg/mL of the pemetrexed diacid; 
 250 mg/mL to 300 mg/mL of the propylene glycol; 
 18 mg/mL to 20 mg/mL of the tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6. 
     
     
       4. The method of  claim 1 , wherein the liquid composition is in a vial. 
     
     
       5. The method of  claim 4 , wherein the vial is a multi-dose vial. 
     
     
       6. A method of treating pleural mesothelioma in a patient in need thereof comprising
 providing a liquid pharmaceutical composition consisting of: 
 20 mg/mL to 30 mg/mL of pemetrexed diacid; 
 200 mg/mL to 300 mg/mL of propylene glycol; 
 12 mg/mL to 24 mg/mL of tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6, wherein the composition is suitable for multi-dose administration, and wherein the composition remains stable when stored for about 14 months at a temperature of 2° C. to 8° C. in a container having a head-space oxygen content of about 20% v/v, such that the composition comprises no more than 3% w/w of total impurities after said storage;
 diluting the liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's Injection, or Lactated Ringer's Injection to form a diluted liquid composition; and 
 intravenously administering the diluted liquid composition to the patient. 
 
     
     
       7. The method of  claim 6 , wherein the liquid pharmaceutical composition consists of:
 25 mg/mL of the pemetrexed diacid; 
 250 mg/mL to 300 mg/mL of the propylene glycol; 
 17 mg/mL to 21 mg/mL of the tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6. 
     
     
       8. The method of  claim 6 , wherein the liquid pharmaceutical composition consists of:
 25 mg/mL of the pemetrexed diacid; 
 250 mg/mL to 300 mg/mL of the propylene glycol; 
 18 mg/mL to 20 mg/mL of the tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6. 
     
     
       9. The method of  claim 6 , wherein the liquid composition is in a vial. 
     
     
       10. The method of  claim 9 , wherein the vial is a multi-dose vial. 
     
     
       11. A method of treating non-squamous, non-small cell lung cancer in a patient in need thereof comprising
 providing a liquid pharmaceutical composition consisting of: 
 20 mg/mL to 30 mg/mL of pemetrexed diacid; 
 200 mg/mL to 300 mg/mL of propylene glycol; 
 12 mg/mL to 24 mg/mL of tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6, wherein the composition is suitable for multi-dose administration, and wherein the composition remains stable when stored for about 14 months at a temperature of 2° ° C. to 8° C. in a container having a head-space oxygen content of about 20% v/v, such that the composition comprises no more than 3% w/w of total impurities after said storage;
 diluting the liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's Injection, or Lactated Ringer's Injection to form a diluted liquid composition; and 
 intravenously administering the diluted liquid composition to the patient. 
 
     
     
       12. The method of  claim 11 , wherein the liquid pharmaceutical composition consists of:
 25 mg/mL of the pemetrexed diacid; 
 250 mg/mL to 300 mg/mL of the propylene glycol; 
 17 mg/mL to 21 mg/mL of the tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6. 
     
     
       13. The method of  claim 11 , wherein the liquid pharmaceutical composition consists of:
 25 mg/mL of the pemetrexed diacid; 
 250 mg/mL to 300 mg/mL of the propylene glycol; 
 18 mg/mL to 20 mg/mL of the tromethamine; 
 optionally HCl; and 
 water, 
 
       wherein the pH of the composition is from about 7.4 to 7.6. 
     
     
       14. The method of  claim 11 , wherein the liquid composition is in a vial. 
     
     
       15. The method of  claim 14 , wherein the vial is a multi-dose vial.